scholarly journals COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

2021 ◽  
Author(s):  
Pauline Maisonnasse ◽  
Yoann Aldon ◽  
Aurélien Marc ◽  
Romain Marlin ◽  
Nathalie Dereuddre-Bosquet ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Neutralizing Antibody ◽  
High Dose ◽  
Preclinical Models ◽  
Viral Loads ◽  
Strong Antiviral Activity ◽  
One Year ◽  
Experimental Findings ◽  
Therapeutic Settings

Abstract One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed1–3. Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals4–6. Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo, a neutralizing antibody isolated from a convalescent patient7 and highly potent against the B.1.1.7. isolate8,9. In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg− 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

scholarly journals COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pauline Maisonnasse ◽  
Yoann Aldon ◽  
Aurélien Marc ◽  
Romain Marlin ◽  
Nathalie Dereuddre-Bosquet ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Neutralizing Antibody ◽  
High Dose ◽  
Preclinical Models ◽  
Viral Loads ◽  
Cynomolgus Macaques ◽  
Strong Antiviral Activity ◽  
Upper Respiratory ◽  
Therapeutic Settings

AbstractEffective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.

scholarly journals Infectious RNA vaccine protects mice against chikungunya virus infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Inga Szurgot ◽  
Karl Ljungberg ◽  
Beate M. Kümmerer ◽  
Peter Liljeström
Keyword(s):  
Chikungunya Virus ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
High Dose ◽  
Vaccine Platform ◽  
Encoding Gene ◽  
Rna Replicon ◽  
Nsp3 Gene

AbstractWe describe a novel vaccine platform that can generate protective immunity to chikungunya virus (CHIKV) in C57BL/6J mice after a single immunization by employing an infectious RNA (iRNA), which upon introduction into a host cell launches an infectious attenuated virus. We and others have previously reported that an engineered deletion of 183 nucleotides in the nsP3 gene attenuates chikungunya virus (CHIKV) and reduces in vivo viral replication and viremia after challenge in mice, macaques and man. Here, we demonstrated that in vitro transfection of iRNA carrying the nsP3 deletion generated infectious viruses, and after intramuscular injection, the iRNA induced robust antibody responses in mice. The iRNA was superior at eliciting binding and neutralizing antibody responses as compared to a DNA vaccine encoding the same RNA (iDNA) or a non-propagating RNA replicon (RREP) lacking the capsid encoding gene. Subsequent challenge with a high dose of CHIKV demonstrated that the antibody responses induced by this vaccine candidate protected animals from viremia. The iRNA approach constitutes a novel vaccine platform with the potential to impact the spread of CHIKV. Moreover, we believe that this approach is likely applicable also to other positive-strand viruses.

Abstract 470: High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL

2020 ◽  
Author(s):  
Caleb Ruiz-Jimenez ◽  
Jacqueline Coats ◽  
Cornelia Stoian ◽  
Ineavely Baez ◽  
Hossam Alkashgari ◽  
...  
Keyword(s):  
Tumor Burden ◽  
High Dose ◽  
Preclinical Models

scholarly journals Effect of HIV-1 Env on SERINC5 Antagonism

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Saina Beitari ◽  
Shilei Ding ◽  
Qinghua Pan ◽  
Andrés Finzi ◽  
Chen Liang
Keyword(s):  
Antiviral Activity ◽  
High Frequency ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Viral Loads ◽  
Virion Incorporation ◽  
Viral Particles ◽  
Ccr5 Inhibitor ◽  
Hiv 1

ABSTRACT SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the HIV-1 Nef protein counters SERINC5 through downregulating SERINC5 from the cell surface and preventing the virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic SERINC5 from being incorporated into HIV-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated SERINC5. Testing of a panel of HIV-1 Env proteins from different subtypes revealed a high frequency of SERINC5-resistant Envs. Interestingly, although the SERINC5-bearing viruses were not inhibited by SERINC5 itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation. IMPORTANCE HIV-1 Nef is known to enhance the infectivity of HIV-1 particles and to contribute to the maintenance of high viral loads in patients. However, the underlying molecular mechanism remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1 but is antagonized by Nef, which prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high levels of SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies in vivo, HIV-1 needs Nef to remove SERINC5 from viral particles, even though viral Env is able to resist virion-associated SERINC5.

scholarly journals Extracellular 2′-5′ Oligoadenylate Synthetase Stimulates RNase L-Independent Antiviral Activity: a Novel Mechanism of Virus-Induced Innate Immunity

2010 ◽  
Vol 84 (22) ◽  
pp. 11898-11904 ◽  
Author(s):  
Helle Kristiansen ◽  
Christina A. Scherer ◽  
Maralee McVean ◽  
Shawn P. Iadonato ◽  
Susanne Vends ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Agent ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Antiviral Compound ◽  
Clinical Prognosis ◽  
Strong Antiviral Activity ◽  
Infected Cells

ABSTRACT The 2′-5′ oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins. However, several studies demonstrate a correlation between the concentration of freely circulating OAS protein in sera from hepatitis C patients and their clinical prognosis. Here we demonstrate that extracellular OAS1 enters into cells and possesses a strong antiviral activity, both in vitro and in vivo, which is independent of RNase L. The OAS protein directly inhibits viral proliferation and does not require the activation of known antiviral signaling pathways. We propose that OAS produced by cells infected with viruses is released to the extracellular space, where it acts as a paracrine antiviral agent. Thus, the OAS protein represents the first direct antiviral compound released by virus-infected cells.

OBR-5-340—A Novel Pyrazolo-Pyrimidine Derivative with Strong Antiviral Activity Against Coxsackievirus B3 In Vitro and In Vivo

2011 ◽  
Vol 90 (2) ◽  
pp. A29 ◽  
Author(s):  
Heike Braun ◽  
Vadim A. Makarov ◽  
Olga B. Riabova ◽  
Elena S. Komarova ◽  
Martina Richter ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Coxsackievirus B3 ◽  
Pyrimidine Derivative ◽  
Strong Antiviral Activity

scholarly journals Systematic assessment of antiviral potency, breadth, and synergy of triple broadly neutralizing antibody combinations against Simian-Human Immunodeficiency Viruses

2020 ◽  
Author(s):  
Stella J Berendam ◽  
Tiffany M Styles ◽  
Papa K Morgan-Asiedu ◽  
DeAnna Tenney ◽  
Amit Kumar ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Systematic Assessment ◽  
Effector Functions ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Antiviral Activities

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term HIV remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the ability of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and non-neutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain-dependent. Moreover, we observe a strong correlation between the neutralization potencies and non-neutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprised of CD4 binding site, V2-glycan, and gp120-gp41 interface targeting bNAbs that are capable of mediating, synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

scholarly journals MOXIDECTIN AND IVERMECTIN INHIBIT SARS-COV-2 REPLICATION IN VERO E6 CELLS BUT NOT IN HUMAN PRIMARY AIRWAY EPITHELIUM CELLS

2021 ◽  
Author(s):  
Nilima Dinesh Kumar ◽  
Bram M. ter Ellen ◽  
Ellen M. Bouma ◽  
Berit Troost ◽  
Denise P. I. van de Pol ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Effect ◽  
Vero Cells ◽  
In Vitro Models ◽  
World Health ◽  
Current Evidence ◽  
High Dose ◽  
Health Organization

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 μM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: “the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive”. It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 μM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

scholarly journals Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

2020 ◽  
Vol 117 (31) ◽  
pp. 18754-18763 ◽  
Author(s):  
Mangaiarkarasi Asokan ◽  
Joana Dias ◽  
Cuiping Liu ◽  
Anna Maximova ◽  
Keenan Ernste ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Antiviral Effect ◽  
Effector Function ◽  
Decay Kinetics ◽  
Plasma Virus

Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

scholarly journals Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

2021 ◽  
Author(s):  
Nilima Dinesh Kumar ◽  
Bram Ter Ellen ◽  
Ellen M Bouma ◽  
Berit Troost ◽  
Denise P. I van de Pol ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Effect ◽  
Vero Cells ◽  
In Vitro Models ◽  
World Health ◽  
Current Evidence ◽  
High Dose ◽  
Health Organization

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 micromolar. These in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: "the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive". It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and a structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 micromolar. These disappointing results calls for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

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